8D0C

Human SARM1 TIR domain bound to NB-3-ADPR

Summary for 8D0C

• Entry DOI: 10.2210/pdb8d0c/pdb
• Related: 8D0D 8D0E 8D0F 8D0G 8D0H 8D0I 8D0J 8D0M
• Descriptor: NAD(+) hydrolase SARM1, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-[4-[(1~{S})-1-[methyl-[2,2,2-tris(fluoranyl)ethylcarbamoyl]amino]ethyl]pyridin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate (3 entities in total)
• Functional Keywords: nad, hydrolase, axon degeneration, neuroscience, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 34018.25

Authors

Bratkowski, M.A.,Mathur, P. (deposition date: 2022-05-26, release date: 2022-09-21, Last modification date: 2023-10-25)

Primary citation

Bratkowski, M.,Burdett, T.C.,Danao, J.,Wang, X.,Mathur, P.,Gu, W.,Beckstead, J.A.,Talreja, S.,Yang, Y.S.,Danko, G.,Park, J.H.,Walton, M.,Brown, S.P.,Tegley, C.M.,Joseph, P.R.B.,Reynolds, C.H.,Sambashivan, S.
Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease.
Neuron, 110:3711-, 2022

PubMed Abstract: Axon degeneration is an early pathological event in many neurological diseases. The identification of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1 as a central metabolic sensor and axon executioner presents an exciting opportunity to develop novel neuroprotective therapies that can prevent or halt the degenerative process, yet limited progress has been made on advancing efficacious inhibitors. We describe a class of NAD-dependent active-site SARM1 inhibitors that function by intercepting NAD hydrolysis and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR). The resulting small-molecule ADPR adducts are highly potent and confer compelling neuroprotection in preclinical models of neurological injury and disease, validating this mode of inhibition as a viable therapeutic strategy. Additionally, we show that the most potent inhibitor of CD38, a related NAD hydrolase, also functions by the same mechanism, further underscoring the broader applicability of this mechanism in developing therapies against this class of enzymes.

PubMed: 36087583
DOI: 10.1016/j.neuron.2022.08.017

Experimental method

X-RAY DIFFRACTION (2.09 Å)